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Severe, sustained pulmonary hypertension is potentially
fatal. It is, however, time to adopt a more positive and
aggressive approach to the management of pulmonary hypertension
in children. Recent advances in genetics and cell biology
provide insights into the pathogenesis of this disease.
New therapies offer an improved quality of life and increased
survival.
The sustained clinical and hemodynamic improvement seen
in many adults and children with primary pulmonary hyperten-sion
(PPH) treated with continuous prostacyclin, and data from
numerous experimental studies indicate that it is possible
to arrest and perhaps even reverse the disease process.
Potential reversal of the disease process is likely to
be greater in the young, in whom the vasculature is still
remodeling. Also, pulmonary vascular reactivity is greater
in children than in adults with pulmonary hypertension,
suggesting greater vasodilator responsiveness and the
possibility of a better therapeutic out-come. When PPH
is untreated, however, its natural history is significantly
worse in children than adults, and even with treat-ment
the disease is less predictable. Unfortunately, most chil-dren
are referred late in the course of the disease, making
it imperative to increase awareness of the condition and
encour-age early referral. It is unclear, however, why
the clinical course varies considerably in different children.
Pulmonary hypertension is defined as a mean pulmonary
arterial pressure > 25mm Hg at rest or 30mm Hg with exercise,
although pulmonary hypertension in childhood is usually
asso-ciated with considerably higher pressures. A new
classification was proposed at a WHO Symposium in 1998,
based on anato-my, clinical features and an appreciation
of the commonality of at least some of the underlying
mechanisms.1 Primary pul-monary hypertension and pulmonary
hypertension related to congenital heart disease, persistent
pulmonary hypertension of the newborn (PPHN), connective
tissue disease, HIV infection, drugs and toxins were grouped
together as ‘pulmonary arterial hypertension’ (PAH). This
new classification encourages the extension of therapeutic
modalities known to be effective in PPH to other forms
of pulmonary hypertension, in both adults and children.
Further clarification is necessary in children with congenital
heart disease. In these children PAH is usually caused
and driven by a cardiac abnormality, which leads to the
development of the Eisenmenger Syndrome. But in some chil-dren
the abnormality is, and always has been, hemodynamical-ly
insignificant. Clinically these children behave as though
they have PPH, and should be treated as such.
Pathogenesis of Pulmonary
Hypertension in Children
During the past few years we have gained considerable
insight into the molecular mechanisms responsible for
the develop-ment and maintenance of PAH, several of which
suggest prom-ising new approaches to therapy.2 This review
focuses on the pathogenesis of the more common forms of
PAH in the young, PPH, PPHN, and pulmonary hypertension
associated with con-genital heart disease. Genetic studies
have concentrated on familial PPH (FPPH) and the mutations
recently identified in FPPH have not yet been sought systematically
in other forms of pulmonary hypertension.
PRIMARY PULMONARY HYPERTENSION:
GENETICS
Familial Primary Pulmonary
Hypertension (FPPH)
Only 6% of cases of PPH have been reported as familial.3
The disease is transmitted as an autosomal dominant trait,
with incomplete penetrance. The chance of a person carrying
a gene for FPPH developing the disease is higher in females
(30%) than males (15%), and a female predominance is present
from early childhood. FPPH shows gene anticipation, the
disease fre-quently presenting at an earlier age in successive
generations.4 The FPPH locus maps to chromosome 2q31-32
and germline mutations have been identified in the bone
morphogenetic pro-tein receptor-II (BMPR2).5 The BMPs
form the largest group within the transforming growth
factor-b (TGF-b) family of cytokines. The PPH disease-associated
mutations identified would be expected to disrupt signaling
pathways mediated by BMPR2, thereby removing a mechanism
for keeping vascular remodeling in check and facilitating
abnormal proliferation of pulmonary vascular cells. Mutation
in another TGF-b family member, the Type I receptor gene,
activin -receptor -like- kinase (ALK1) has been implicated
in Hereditary Hemorrhagic Telangectasia associated pulmonary
hypertension.6 It is likely that other PPH genes remain
to be identified. BMPR2 muta-tions have not been identified
in some 60% of FPPH cases, and most sporadic cases do
not appear to harbor BMPR2 mutations. There are also families
in whom pulmonary hypertension is associated with hemoglobinophathies
and platelet storage defects. Sporadic Primary Pulmonary
Pulmonary Hypertension BMPR2 defects have been described
in 26% of sporadic cases of PPH, in some cases arising
as “de novo” or spontaneous, mutations.7
Pathobiology
Sporadic and familial PPH have the same pathological features.
At autopsy, most adults and older children have advanced
pul-monary vascular obstructive disease with plexiform
lesions, and this picture can be seen before 3 years of
age (Fig. 1).
Monoclonal cell expansion is thought to lead to the production
of plexiform lesions in a subset of adult patients with
PPH.8 In young children, the cellular changes can be restricted
to severe pulmonary arterial medial hypertrophy with marked
intimal pro-liferation, lesions that are more likely to
be potentially reversible. The instigators of this process
are uncertain. Loss of one normal BMPR2 allele does not,
in itself, produce the phe-notype. It is now thought that
PPH affects those with a genetic predisposition to respond
adversely to a variety of stimuli and that the clinical
and structural findings represent the final common pathway.
The following are thought important in the pathogenesis
of PPH:
- Endothelial dysfunction: Levels of circulating endothelin,
a powerful vasoconstrictor and mitogen, are elevated
and expression of endothelin converting enzyme is increased.
Prostacyclin and nitric oxide, vasodilators with antiprolifer-ative
and antimigratory properties, are reduced.9 Long-term
treatment with prostacyclin or one of its analogues
is a proven, effective therapy 10 while inhaled NO,
NO donors, and the phosphodiesterase inhibitors are
as yet unproved alternatives/adjuncts, unproven in terms
of both efficacy and safety. Endothelin receptor antagonists
have proved safe and effective in small trials, mostly
in adult patients, and are being evaluated in younger
patients.11
- Intense vasoconstriction is thought to be an early,
common response to injury. Although pulmonary vascular
disease is usually well advanced at presentation, the
pulmonary vas-cular resistance falls in some patients
on acute vasodilator testing, more often in children
(50% to 60%) than in adults (20%).12 Calcium channel
blockers, an accepted, conventional therapy, prolongs
survival in adults. Both hypoxia and anorexic agents,
which can cause pulmonary hypertension, inhibit potassium
currents in pulmonary artery smooth muscle cells causing
membrane depolariza-tion, which promotes an increase
in intracellular calcium concentration and hence, vasoconstriction.
Finding dys-functional voltage-gated potassium channels
in primary but not secondary pulmonary hypertension
suggests that potas-sium channels may play a significant
role in the pathogen-esis of PPH. In terms of potential
therapy, ATP-sensitive potassium channel openers probably
offer the greatest promise since these agents are potent
dilators of the pul-monary circulation and are still
able to promote membrane hyperpolarization in proliferating
smooth muscle cells.13
- Platelet function: The ratio of thromboxane to prostacyclin
is increased, predisposing to vasoconstriction and platelet
aggregation.9 The role of serotonin in the pathogenesis
of PPH is still uncertain, but elevated plasma levels
and impaired platelet storage of serotonin can occur.
Serotonin transporters are overexpressed on pulmonary
arterial smooth muscle cells.14 Elevated fibrinopeptide
A levels and pathological studies indicate thrombosis
in situ, and there is evidence of impaired local fibrinolysis.
Anticoagulation increases survival in adults and is
used in children.
- Dysfunction of the immune system: Pulmonary hyperten-sion
is a component of several autoimmune disorders, par-ticularly
scleroderma and appears to have an autoimmune origin
in some children.
PERSISTENT PULMONARY HYPERTENSION
OF THE NEWBORN
Failure of the pulmonary circulation to adapt normally
to extra-uterine life causes PPHN. The condition can be
idiopathic but this is rare, and it is more commonly associated
with congeni-tal and acquired hypoxic lung disease and
congenital heart defects. The condition has a high morbidity
and mortality despite the advent of inhaled nitric oxide
therapy. Irrespective of etiology, during the first few
days of life the intrapulmonary arterial wall structure
is similar to that seen in fetal life and neonatal remodeling
is impaired.15 Functional studies demon-strate impairment
of the NO pathway, sometimes a deficiency of the NO substrate
L-arginine, increased levels of the endoge-nous inhibitor
asymmetric dimethyl arginine, and persistently high circulating
endothelin levels. Studies on normal animals reveal low
NOS activity and relatively poor endothelial depend-ent
relaxation at birth, and these systems fail to mature
prop-erly in PPHN.16
Different relaxation pathways (NO, prostaglandin, EDHF)
mature at different rates and have different vulnerabilities
to insult. Vasoconstrictor ET-A receptor density increases
and endothelial vasodilator ET-B receptor density decreases.17
Thus, failure to reduce the pulmonary vascular resistance
after birth appears to involve a primary structural abnormality,
failure of endothelial dependent +/- independent relaxation,
and an excess of vasoconstrictor activity. The rationale
for giving NO and phosphodiesterase inhibitors is that
there is an absolute or relative lack of the endogenous
substance. Oxygenation usually improves with administration
of NO and the availability of NO has reduced the need
for extracorporeal membrane oxygena-tion. New strategies
directed at antagonizing vasoconstriction and modifying
smooth muscle cell cytoskeletal remodeling are indicated.
Outcome depends on causality. Some babies who appeared
to recover normally were later found to have persist-ent
arterial medial hypertrophy. The relationship between
PPHN and PPH is uncertain but children who present with
PPH during the first years of life fre-quently have a
history that suggests that they were pulmonary hypertensive
from birth. Occasionally an infant thought to have PPH
is found to have a secundum atrial septal defect. This
is usually an incidental, though protective abnormality,
and should not be closed.
Congenital Heart Disease
The rate at which pulmonary vascular disease develops
in chil-dren with congenital heart disease depends on
the type of intracardiac abnormality, but some exceptional
children appear to be genetically predisposed to develop
an accelerated form of the disease. Endothelial cell damage,
medial smooth muscle cell hyperplasia, hypertrophy and
site-specific changes in cell phenotype are well described
in early infancy 2 (Fig. 1). Respiratory unit arteries,
about half of which normally form after birth, are reduced
in size and number. This is the mor-phological substrate
of pulmonary hypertensive crises, which most often occur
in the presence of potentially reversible struc-tural
abnormalities. Endothelial dysfunction is present early.
In potentially operable children the relaxation response
to acetylcholine is impaired, basal NO production may
be elevat-ed initially but then decreases, and the ratio
of thromboxane to prostacyclin is elevated.18 Impaired
endothelial-dependent relaxation occurs later in association
with elevation in resist-ance. Dilatation and plexiform
lesions contain abundant VEGF, which may help ensure continued
perfusion of the capillary bed since VEGF helps induce
endothelium dependent relaxation.19 VEGF is also a potent
angiogenic factor. It co-localizes with TGF-ß in the arterial
wall and TGF-ß upregulates its angiogenic activity in
vitro. As intimal obstruction develops, flow becomes more
turbulent and in vitro studies suggest that this is likely
to unfavorably influence gene transcription. Laminar flow
is asso-ciated with activation of genes such as eNOS and
COX2 but tur-bulent flow is associated with the localized
upregulation of VCAM-1 and ICAM-1, encouraging leucocyte
recruitment and activation.20,21 Changes in mechanical
stress also alter expres-sion of specific genes in the
smooth muscle cell, such as PDGF.
Postoperative pulmonary hypertension. The patient with
repaired congenital heart disease who has pulmonary hyperten-sion
effectively has PPH, with the added problem of a compro-mised
myocardium. Survival is significantly worse in the untreated
patient with PPH than in most patients with the Eisenmenger
syndrome. Assuming that these patients cannot be helped
by further surgery, they should generally be treated as
though they had PPH, and without delay.
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